Plasmodium falciparum infection during pregnancy results in placental malaria (PM). In Africa alone, ~25 million women yearly are at risk of developing PM, which causes ~100,000 infant and tens of thousand maternal deaths. Low birth weight is common in PM and these newborns are highly vulnerable to death from subsequent malaria or other infections. Although people in endemic areas will have acquired protective immunity against malaria by their adulthood, women are susceptible to severe malaria during pregnancy. This is due to the adherence in the placenta of an antigenically distinctive P. falciparum phenotype. So women who have never been pregnant have no immunity to this parasite phenotype. In their first and second pregnancies women infected with P. falciparum, the adherent parasites are selected in the placenta, grow rapidly, allowing infected red blood cells (RBCs) to accumulate to high density in the placenta. This results in inflammation and placental dysfunction, causing PM. An effective treatment to prevent or treat PM is essential, but is not currently available. The parasite exports a variant adhesive protein called VAR2CSA, a member of Plasmodium falciparum erythrocyte membrane protein 1 family, that is displayed on the erythrocyte surface. The ectodomain of VA2CSA mediates the binding of IRBCs to 12-mer motifs of the chondroitin 4-sulfate (C4S) moieties of the CSPG receptor in the placenta. Women who have acquired inhibitory anti-VAR2CSA antibodies during prior pregnancies are resistant to PM and deliver healthy babies, indicating that blocking of IRBC adherence is a suitable strategy to treat PM. However, VAR2CSA is a highly polymorphic and so, obtaining a viable vaccine requires rationale design based on the knowledge of conserved C4S-binding site. An alternative approach is to develop adherence-blocking inhibitors. Since VAR2CSA is on the IRBC surface and is accessible for even highly polar molecules, this is predicted to be highly promising strategy. Accordingly, the goals of this proposal are to: (i) chemically synthesize the C4S 12-mers containing two sulfate residues at specific positions and a library of chondroitin sulfate oligosaccharides of different size and sulfation patterns. This will enable us to identify the optimally binding oligosaccharide and critical interactions involved in VAR2CSA-C4S binding; (ii) Using the novel and sensitive C4S 12-mer-based fluorescence anisotropy assay that we have already developed, we will screen drug and glycosaminoglycan mimetic libraries to identify, by high-throughput screening, small molecule inhibitors that block VAR2CSA-C4S binding and validate the inhibitors by a cell-based assay (iii) characterize the C4S-binding sites in VAR2CSA to identify the interacting amino acid residues. The results are expected to provide critical information necessary for developing therapeutics for PM. The long-term objective is to develop small molecule inhibitors that can be used for PM treatment.